In the United States and in many Western countries, lung cancer represents the leading cause of cancer-related death (Jemal, A. et al. Cancer Statistics 2006. CA Cancer J. Clin. 56, 106-130 (2006). The National Cancer Institute of the U.S. National Institutes of Health estimated there were 215,020 new cases of lung cancer and 161,840 lung cancer-related deaths within the U.S. in 2008. Lung cells cancers are classified into two main types, small cell lung cancer (SCLC) and non small cell lung cancer (NSCLC).
Cell classification and typing is typically performed using light microscopy, immunohistochemistry, physical examination, chest x-ray, and chest computed tomography (CT) scan with infusion of contrast material. Diagnosis generally requires review of pathologic material by an experienced lung cancer pathologist to manually assess the number of mitotic cells in a histological slide prepared from the tumor. Tumor classification is vitally important because small cell lung cancer, which responds well to chemotherapy and is generally not treated surgically, can be confused on microscopic examination with non-small cell carcinoma, for which treatment normally consisting of surgical resection. Additionally, staging procedures are important to distinguish localization and tumor aggressiveness. Determining cancer stage non-surgically provides better assessment of prognosis, and aides in treatment determination, which is usually influenced by stage, particularly when chest radiation therapy or surgical excision is added to chemotherapy for patients with limited-stage disease.
SCLCs are the most aggressive pulmonary tumor, with median survival from diagnosis of 2 to 4 months. Localized (limited) SCLC tumors are confined to the hemithorax of origin, the mediastinum, or the supraclavicular lymph nodes, and treatment includes surgical rescission, with or without chemotherapy. Extensive-stage disease, where tumor has spread beyond the supraclavicular area, possess worse prognosis than limited-stage tumors.
NSCLCs are a heterogeneous aggregate of tumors, with the most common histologies epidermoid or squamous carcinoma, adenocarcinoma, and large cell carcinoma. These histologies are often classified together because approaches to diagnosis, staging, prognosis, and treatment are similar. The first classification of tumors are surgically resectable (generally stage I, stage II, and selected stage III tumors), and possess the best prognosis, which depends on a variety of tumor and host factors. In some cases, tumors are alternatively treated with curative radiation therapy or chemotherapy. The second group of tumors is locally (T3-T4) and/or regionally (N2-N3) advanced lung cancer, which are treated with combination therapies, such as radiation therapy in combination with chemotherapy or surgical resection and either preoperative or postoperative chemotherapy or chemoradiation therapy. The final tumor group is metastatic tumor with distant metastasis (M1) at the time of diagnosis. Current treatment is radiation therapy or chemotherapy for palliation.
The 5-year, overall survival rate of 15% has not improved over many decades, mainly because approximately two-thirds of lung cancers are discovered in advanced stages, for which cure by surgical resection is no longer an option. Furthermore, even among early-stage patients who are treated to primarily by surgery with curative intent, 30-55% will develop and die of metastatic recurrence. Recent multinational clinical trials (IALT, JBR10, ANITA, UFT, LACE) conducted in several continents have demonstrated that adjuvant chemotherapy significantly improves the survival of patients with early-stage (IB-II) disease (Booth, C. M. & Shapard F. A. Adjuvant chemotherapy for resected non-small cell lung cancer. J. Thorac. Oncol. 2, 180-187 (2006)). Nevertheless, it is clear that a proportion of patients with stage I disease have poorer prognosis and may benefit significantly from adjuvant chemotherapy, whereas some with stage II disease with relatively good prognoses may not benefit significantly from adjuvant chemotherapies. It remains possible, however, that the latter patients could derive additional benefit from adjuvant targeted therapies (Booth, C. M. & Shepherd, F. A. Adjuvant chemotherapy for resected non-small cell lung cancer. J. Thorac. Oncol. 2, 180-187 (2006); Gandara, D. R., et al., Adjuvant chemotherapy of stage I non-small cell lung cancer in North America. J. Thorac. Oncol. 7(suppl. 3), S125-S127 (2007); Shepherd, F. A., et al. Erlotinib in previously treated non-small-cell lung cancer. N. Engl. J. Med. 353, 123-132 (2005)).
Therefore, there is an urgent need to establish new diagnostic paradigms and validate in clinical trials methods for improving the selection of stage I-II patients who are most likely to benefit from adjuvant chemotherapy.